ORGANIC LETTERS XXXX Vol. XX, No. XX 000–000
Environmentally Benign Synthesis of Indeno[1,2‑b]quinolines via an Intramolecular Povarov Reaction Ming Chen, Ning Sun, and Yuanhong Liu* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China
[email protected] Received September 25, 2013
ABSTRACT
A new synthetic route to indeno[1,2-b]quinolines via reactions of o-propargylbenzaldehydes with N-aryl amines based on an intramolecular azaDiels Alder (Povarov) reaction has been developed. This method offers several advantages such as no requirement for an oxidant, high efficiency, and a wide reaction scope.
Quinoline ring systems occur widely in natural products, and many of them show interesting biological activities.1 In particular, quinoline rings condensed with various heterocycles or carbocycles are of significant interest since they have been found to be potentially useful as anticancer agents by acting as DNA ligands.2 For example, indenoquinoline A possesses cytotoxic properties with in vivo activity in colon 38 tumors.2c Indenoquinoline B exhibits cytotoxicities comparable to that of camptothecin against (1) (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605. (b) Balasubramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 5, p 245. (2) (a) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888. (b) Werbovetz, K. A.; Bhattacharjee, A. K.; Brendle, J. J.; Scovill, J. P. Bioorg. Med. Chem. 2000, 8, 1741. (c) Deady, L. W.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1997, 40, 2040. (d) Chakrabarty, S.; Croft, M. S.; Marko, M. G.; Moyna, G. Bioorg. Med. Chem. 2013, 21, 1143. (e) Deady, L. W.; Desneves, J.; Kaye, A. J.; Thompson, M.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 1999, 7, 2801. (f) Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2001, 9, 445. (g) Chen, J.; Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2000, 8, 2461. (h) Chen, J.; Deady, L. W.; Kaye, A. J.; Finlay, G. J.; Bruce, C.; Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2002, 10, 2381. (i) Mekapati, S. B.; Denny, W. A.; Kurup, A.; Hansch, C. Bioorg. Med. Chem. 2001, 9, 2757. (j) Yamato, M.; Takeuchi, Y.; Hashigaki, K.; Ikeda, Y.; Ming-rong, C.; Takeuchi, K.; Matsushima, M.; Tsuruo, T.; Tashiro, T.; Tsukagoshi, S.; Yamashita, Y.; Nakano, H. J. Med. Chem. 1989, 32, 1295.
MCF-7 cells2d (Figure 1). Owing to their biological importance, much effort has been devoted to develop more efficient and convenient strategies for the synthesis of quinolines.3 Classical methods, such as Skraup,4a Combes,4b Friedl€ander,4c Pfitzinger,4d and Doebner von Miller4e reactions, are frequently employed. However, usually they do not allow the formation of quinolines with (3) For reviews, see: (a) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New York, 1996; Vol. 5, p 167. (b) Kouznetsov, V. V.; Mendez, L. Y. V.; G omez, C. M. M. Curr. Org. Chem. 2005, 9, 141. For recent developments in the synthesis of quinolines, see: (c) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109. (d) Zhang, X.; Campo, M. A.; Larock, R. C. Org. Lett. 2005, 7, 763. (e) Luo, Y.; Li, Z.; Li, C.-J. Org. Lett. 2005, 7, 2675. (f) Morel, A. F.; Larghi, E. L.; Selvero, M. M. Synlett 2005, 2755. (g) Tanaka, S. Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71, 800. (h) Jia, C. S.; Zhang, Z.; Tu, S. J.; Wang, G. W. Org. Biomol. Chem. 2006, 4, 104. (i) Wu, J.; Xia, H. G.; Gao, K. Org. Biomol. Chem. 2006, 4, 126. (j) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72, 6873. (k) Horn, J.; Marsden, S.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117 and references cited therein. (l) Vander Mierde, H.; van der Voort, P.; De Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 1625. (m) Lekhok, K. C.; Prajapati, D.; Boruah, R. C. Synlett 2008, 655. (4) (a) Skraup, H. Chem. Ber. 1880, 13, 2086. (b) Combes, A. Bull. Chim. Soc. France 1888, 49, 89. (c) Friedl€ander, P. Chem. Ber. 1882, 15, 2572. (d) Pfitzinger, W. J. Prakt. Chem. 1886, 33, 100. (e) Doebner, O.; von Miller, W. Chem. Ber. 1881, 14, 2812. (5) (a) Povarov, L. S.; Mikhailov, B. M. Izv. Akad. Nauk SSSR, Ser. Khim. 1963, 953. (b) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656. (c) For a review, see: Kouznetsov, V. V. Tetrahedron 2009, 65, 2721. 10.1021/ol402775k
r XXXX American Chemical Society
Scheme 1. Synthesis of Quinolines through the Povarov Reaction
Figure 1. Biologically active indeno[1,2-b]quinolines.
5 7
wide diversity. Recently, the Povarov reaction, an inverse electron-demand aza-Diels Alder (IED-DA) reaction of N-aryl imines derived from aldehydes and anilines with electron-rich olefins, became one of the most efficient protocols for quinoline preparation (Scheme 1). Alkynes could also be used as dienophiles in a Povarov reaction, although it is much less common than that of alkenes.7 To furnish the quinoline structure, further oxidation of the initial formed tetrahydro/dihydroquinoline under aerobic conditions or using an additional oxidant is often needed. The imine substrate is also known to act as an oxidant by accepting hydrogen in the presence of acid catalyst, and the corresponding reduction product, the amine, would be a byproduct.6n,o,7f,7g,7i The Povarov reaction usually requires a Lewis acid or protic acid such as BF3 3 Et2O, SnCl4, lanthanide triflates, Tf2NH, or p-trifluoroacetic acid to activate the imine substrates, with the reactions under catalyst-free conditions being quite rare. Nevertheless, the development of more simple and practical methods with wide diversity is highly desired. In this communication, we present a novel synthetic route to indeno[1,2-b]quinolines via reaction of o-propargylbenzaldehydes with (6) For a Povarov reaction with alkenes as dienophiles, see: (a) Laschat, S.; Lauterweine, J. J. Org. Chem. 1993, 58, 2856. (b) Beifuss, U.; Herde, A.; Ledderhose, S. Chem. Commun. 1996, 1213. (c) Znang, D.; Kiselyov, A. S. Synlett 2001, 1173. (d) Sundararajan, G.; N. Prabagaran, N.; Varghese, B. Org. Lett. 2001, 3, 1973. (e) Magomedov, N. A. Org. Lett. 2003, 5, 2509. (f) Anniyappan, M.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2003, 44, 3653. (g) Hermitage, S.; Howard, J. A. K.; Jay, D.; Pritchard, R. G.; Probert, M. R.; Whiting, A. Org. Biomol. Chem. 2004, 2451. (h) Yadav, J. S.; Reddy, B. V. S.; Chetia, L.; Srinivasulu, G.; Kunwar, A. C. Tetrahedron Lett. 2005, 46, 1039. (i) Jimenez, O.; de la Rosa, G.; Lavilla, R. Angew. Chem., Int. Ed. 2005, 44, 6521. (j) Savitha, G.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 3589. (k) Muhuhi, J.; Spaller, M. R. J. Org. Chem. 2006, 71, 5515. (l) Zhou, J.; Magomedov, N. A. J. Org. Chem. 2007, 72, 3808. (m) Hirashita, T.; Kawai, D.; Araki, S. Tetrahedron Lett. 2007, 48, 5421. (n) Shindoh, N.; Tokuyama, H.; Takasu, K. Tetrahedron Lett. 2007, 48, 4749. (o) Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K. J. Org. Chem. 2008, 73, 7451. (p) Gaddam, V.; Nagarajan, R. Org. Lett. 2008, 10, 1975. (q) Desrat, S.; van de Weghe, P. J. Org. Chem. 2009, 74, 6728. (r) Dagousset, G.; Zhu, J.; Masson, G. J. Am. Chem. Soc. 2011, 133, 14804. (7) For a Povarov reaction with alkynes as dienophiles, see: (a) Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.; Ruggieri, F. J. Org. Chem. 1992, 57, 1842. (b) Bortoloffl, B.; Leardini, R.; Nanni, D.; Zanardi, G. Tetrahedron 1993, 49, 10157. (c) Baudelle, R.; Melnyk, P.; Deprez, B.; Tartar, A. Tetrahedron 1998, 54, 4125. (d) Heather Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913. (e) Zhou, H.-B.; Liu, G.-S.; Yao, Z. -J. Org. Lett. 2007, 9, 2003. (f) Zhao, Y.; Zhang, W.; Wang, S.; Liu, Q. J. Org. Chem. 2007, 72, 4985. (g) Gaddam, V.; Ramesh, S.; Nagarajan, R. Tetrahedron 2010, 66, 4218. (h) Suresh, R.; Muthusubramanian, S.; Senthilkumaran, R.; Manickam, G. J. Org. Chem. 2012, 77, 1468. (i) Pericherla, K.; Kumar, A.; Jha, A. Org. Lett. 2013, 15, 4078. B
Scheme 2. Synthesis of Indeno[1,2-b]quinolines without the Use of Oxidant
N-aryl amines; it is based on the intramolecular Povarov reaction (Scheme 2). During our studies of transition-metal-catalyzed transformations of propargyl carboxylates,8 we occasionally found that the reaction of o-propargylbenzaldehyde 1a with 2 equiv of aniline in DCE at 80 °C for 23 h afforded, unexpectedly, a ring-condensed product of indeno[1,2-b]quinoline 2a in 38% yield (Table 1, entry 1). The unique structural features and potential bioactivity of indenoquinolines prompted us to investigate this condensation reaction under various conditions. The results are summarized in Table 1. To our delight, in the presence of 4 A˚ molecular sieves (Alfa, 3 5 mm beads, 30 grains, ca. 1.5 g for 0.3 mmol scale) as a water-removing agent, 86% of 2a was obtained in DCE at 80 °C for 8 h (entry 2). Using 1.0 equiv of aniline, the yield of 2a was reduced to 69% (entry 3). Decreasing the amount of molecular sieves resulted in a slightly lower yield of 2a (83%, entry 5, ca. 1.0 g 4 A˚ molecular sieves was used). The solvent effect was also examined. The reaction could proceed in toluene, where 79% of the desired product 2a was obtained (entry 6). However, the use of EtOH gave only a complex reaction mixture (entry 7). In order to understand the effect of protecting groups, reactions were carried out with Bz (1b), Ac (1c), and CO2Me (1d) protected substrates. The reaction proceeded smoothly in these cases, with the yields of 2a ranging from 58% to 83% (entries 8 10). With the optimized reaction conditions in hand, we next investigated the reaction scope of this methodology. During this process, we found that when Piv-protected substrates were employed, in some cases, it was difficult to obtain the desired products with high purity. However, the use of Bz-protected substrates could circumvent the purification problem. Thus we also used Bz-protected (8) (a) Chen, Y.; Chen, M.; Liu, Y. Angew. Chem., Int. Ed. 2012, 51, 6493. (b) Chen, M.; Y. Chen, Y.; Liu, Y. Chem. Commun. 2012, 48, 12189. (c) Chen, M.; Liu, J.; Wang, L.; Zhou, X.; Liu, Y. Chem. Commun. 2013, 49, 8650. Org. Lett., Vol. XX, No. XX, XXXX
Scheme 3. Scope of N-Aryl Aminesa
Table 1. Optimization Studies for the Formation of Indenoquinoline 2a
entry
R
MS (g)
solvent
temp (°C)
time (h)
yield (%)a
1 2 3b 4 5 6 7 8 9 10
Piv (1a) Piv (1a) Piv (1a) Piv (1a) Piv (1a) Piv (1a) Piv (1a) Bz (1b) Ac (1c) COOMe (1d)
ca. 1.5 ca. 1.5 ca. 1.5 ca. 1.0 ca. 1.5 ca. 1.5 ca. 1.5 ca. 1.5 ca. 1.5
DCE DCE DCE DCE DCE toluene EtOH DCE DCE DCE
80 80 80 50 80 80 80 80 80 80
23 8 9 9 6 4.5 9.5 7 7 7
38 86 69 82 83 79
c
c
83 68 58
a 0.3 mmol scale. Isolated yields. b 1.0 equiv of PhNH2 was used. Complex reaction mixture was observed.
o-propargylbenzaldehydes as substrates in some cases to examine the reaction scope. As shown in Schemes 3 and 4, a wide variety of diversely substituted o-propargylbenzaldehydes and N-aryl amines were suitable for this reaction, furnishing the desired indeno[1,2-b]quinolines in generally good-to-high yields. We first examined the scope of N-aryl amine substrates (Scheme 3). The results indicated that both electron-poor and -rich aryl substituents were tolerated well, and the electronic nature on N-aryl rings did not have a strong influence on this reaction. For example, p-F, p-Cl, p-Br, p-CF3, and p-CO2Me substituted anilines afforded the corresponding products 2b 2d and 2g 2h in 68 84% yields. p-tBu and p-MeO-substituted anilines provided the corresponding 2i and 2k also in good yields of 67% and 77%, respectively. Ortho-substituted N-aryl amines such as 2-fluorobenzenamine or 2-isopropylbenzenamine afforded 2e or 2j in the same yield of 77%. However, the use of 2-iodobenzenamine resulted in only a 46% yield of 2f. Meta-substituted anilines, such as 3,4,5trimethoxybenzenamine underwent the reaction well with 1a to afford 2l in a high yield of 92%. When naphthalen-1amine was used, a pentacyclic compound 2m was obtained in 75% yield. Next, we examined the substituent effect (R1) on the alkyne terminus (Scheme 4). Substrates with weak electron-withdrawing groups such as p-Cl on the aryl ring afforded 2n in 76% yield, whereas with strong-electronwithdrawing groups, such as p-CF3 or p-CO2Et, the formation of 2o and 2p occurred in lower yields of 60% and 51%, respectively. The electron-rich p-MeO-substituted (9) (a) Reference 2h. (b) Malecki, N.; Carato, P.; Rigo, B.; Goossens, J.; Houssin, R.; Baillyc, C.; Henicharta, J. Bioorg. Med. Chem. 2004, 12, 641. (c) Waldmann, H.; Karunakar, G. V.; Kumar, K. Org. Lett. 2008, 10, 2159. (d) Mohammadi, A. A.; Azizian, J.; Hadadzahmatkesh, A.; Asghariganjeh, M. R. Heterocycles 2008, 75, 947. (e) Yang, D.; Jiang, K.; Li, J.; Xu, F. Tetrahedron 2007, 63, 7654. Org. Lett., Vol. XX, No. XX, XXXX
a Isolated yields. Substrate 1a was used for 2a, 2c, 2i, 2j, and 2l. Substrate 1b was used for 2b, 2d h, 2k, and 2m.
Scheme 4. Scope of o-Propargylbenzaldehydesa
a
Isolated yields.
aryl alkyne provided 2q in 71% yield. The results indicated that the electronic nature of the aryl rings on the alkyne terminus has a strong influence on this reaction. The 2-thienyl group was also compatible with this reaction, leading to 2r in 75% yield. In addition, alkyl-substituted alkynes were also well accommodated. For example, an n Bu- or cyclopropyl-substituted alkynes afforded 2s and 2t in 71% and 57% yields, respectively. Most of the above indenoquinoline products are fluorescent, which could find utility also in organic materials synthesis. It should (10) See Supporting Information. C
Scheme 5. Formation of Polycyclic Compound and Further Transformation
Scheme 6. Possible Reaction Mechanism
subjected to the oxidation conditions.11 It was found that the indeno[1,2-b]quinolin-11-one 4 was formed smoothly via oxidation of the bridged CH2 group. We proposed the following reaction mechanism for this reaction (Scheme 6). First, an imine 5 is formed via condensation of aldehyde 1 with aniline. Then an aza-Diels Alder reaction (Povarov reaction) of the aza-diene moiety with the alkyne occurs to give a cyclized intermediate 6. Subsequently, elimination of the OBz group12 followed by double bond isomerization furnishes the final indenoquinoline 2. In these reactions, no oxidant is required, since aromatization can be achieved by elimination of a leaving group and isomerization. To understand the mechanism, the imine intermediate 5a was isolated in 84% yield under controlled reaction conditions. 5a cyclized under similar reaction conditions to afford 2a in 90% yield (Scheme 7). These results supported our proposed mechanism.
Scheme 7. Control Experiments
be noted that although indeno[1,2-b]quinolines can be prepared by the Pfitzinger reaction between an appropriate isatin and 1-indanone2c,e g or a Friedl€ ander reaction between a 2-aminobenzaldehyde or 2-aminoaryl ketone and 1-indanone,9 the availability of the substrates employed in these methods can be quite limited, which restricts the structural elaboration of the indeno[1,2-b]quinolines, especially, on the quinoline ring moiety. The structures of 2h, 2l, and 2m were unambiguously determined by X-ray crystallography.10 Interestingly, when benzene-1,4-diamine was employed, a hepta-fused-heterocyclic compound 3 was obtained in 42% yield as the major product, in which the second ring closure occurred at the C-1 position of the N-phenyl ring, but not at the C-2 position (Scheme 5). The structure of 3 was also confirmed by X-ray crystallography.10 The regioselectivity in this case can be rationalized by invoking π-stacking of the aromatic groups during the second ringclosing process, leading to indenoquinoline 3 with two phenyl groups on the same side. To demonstrate the synthetic utility of indenoquinoline 2, compound 2a was
In summary, we have successfully developed a facile synthetic strategy for indeno[1,2-b]quinolines based on an intramolecular Povarov reaction. Our reactions proceeded efficiently in the absence of oxidants. Aromatization was achieved by elimination of a leaving group and isomerization. A wide variety of substituents could be incorporated, which allows for a convenient structural modification of simple indenoquinolines. Further studies to extend the scope of the synthetic utility involving an intermolecular Povarov reaction are in progress in our laboratory. Acknowledgment. We thank the National Natural Science Foundation of China (Grant Nos. 21125210, 21372244, 21121062), Chinese Academy of Science and the Major State Basic Research Development Program (Grant No. 2011CB808700) for financial support. Supporting Information Available. Experimental details, spectroscopic characterization of all new compounds, and X-ray crystallography of compounds 2h, 2l, 2m, and 3 are given. This material is available free of charge via the Internet at http://pubs.acs.org. (12) Cao, J.; Yang, X.; Hua, X.; Deng, Y.; Lai, G. Org. Lett. 2011, 13, 478.
(11) Nitta, M.; Ohnuma, M.; lino, Y. J. Chem. Soc., Perkin Trans. 1 1991, 1115.
D
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
